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DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are genetically modified G-protein coupled receptors (GPCRs) that are activated by physiologically inert designer synthetic ligands (designer drugs), known as DREADD ligands. They can be used to modulate neuronal activity, and also to investigate GPCR signaling pathways.
|Cat. No.||Product Name / Activity|
|Activator of muscarinic DREADDs|
|6329||Clozapine N-oxide dihydrochloride|
|Activator of muscarinic DREADDs; water soluble version of Clozapine N-oxide (Cat. No. 4936)|
|5548||DREADD agonist 21|
|Potent muscarinic DREADD agonist|
|6422||DREADD agonist 21 dihydrochloride|
|Potent muscarinic DREADD agonist; water soluble version of DREADD agonist 21 (Cat. No. 5548)|
|Highly potent hM4Di activator; also 5-HT2A and D2 antagonist|
|Potent muscarinc DREADD agonist|
|Activates the κ-opioid DREADD (KORD)|
|Activator of hFFA2-DREADDs|
Studies have provided evidence that DREADDs are functionally similar to their wild type receptors, therefore they are useful tools for the study of GPCR signaling.
The first DREADDs to be developed were derived from human muscarinic acetylcholine receptors (mAChRs) and termed hM1-5D. These receptors have mutations in their orthosteric binding site, abolishing their affinity for the endogenous ligand ACh, while rendering them responsive to the small molecule clozapine-N-oxide (CNO). CNO exhibits no appreciable affinity (Ki >1 μM) for any other relevant CNS target, and therefore is a selective tool for the activation of DREADDs.
Figure 1: Binding of DREADD ligands to Gαq-DREADDs provokes neuronal firing, whereas binding to Gαi-DREADDs results in inhibition of neuronal activity. Clozapine N-oxide dihydrochloride and DREADD agonist 21 are non-selective muscarinic DREADD agonists and so can activate or inhibit neuronal activity, depending on the specific receptor being expressed. Salvinorin B is selective for the KORD receptor, which is coupled to Gαi signaling; consequently binding results in inhibition of neuronal activity.
DREADDs have been shown to be effective for the modulation of neuronal activity. hM3Dq is a Gq-coupled GPCR that activates neuronal firing upon CNO stimulation, while hM4Di is a Gi-coupled GPCR that inhibits neuronal firing through activation of GIRK (Kir3) channels. These DREADDs have also been shown to have applications in vivo. Activation of hM3Dq expressing locus coeruleus neurons by CNO enhanced memory in a mouse model of Down syndrome. Furthermore injection of hM3Dq into the paraventricular hypothalamus (PVH) suppressed hyperphagia in PVH LMO4-deficient obese mice, with activation of hM4Di having the opposite effect.
A new DREADD has since been developed from the κ opioid receptor (KOR), and termed KORD. KORD is activated by the pharmacologically inert small molecule salvinorin B, and will enable the simultaneous interrogation of KOR and mAChR signaling. The development of further DREADDs and small molecule DREADD modulators is currently ongoing.
Tocris offers the following scientific literature for DREADD Ligands to showcase our products. We invite you to request* or download your copy today!
*Please note that Tocris will only send literature to established scientific business / institute addresses.
Produced by Tocris, the chemogenetics research bulletin provides an introduction to chemogenetic methods to manipulate neuronal activity. It outlines the development of RASSLs, DREADDs and PSAMs, and the use of chemogenetic compounds. DREADD ligands and PSEMs available from Tocris are highlighted.
GPCRs can interact with multiple distinct transducers or regulatory proteins and these can be preferentially engaged in an agonist-specific manner giving rise to biased agonism. This poster discusses cutting edge GPCR signaling pharmacology and highlights therapeutic applications of biased agonism.